This work is directed toward developing a therapy that can be used to prevent the pathogenic effects of variola, the agent of smallpox. The possibility of developing this therapy has arisen from research on vaccinia, a close relative of variola. When vaccinia is given to mice, they die in 4-8 days, depending on viral dosage. A small protein produced by vaccinia, E3L, is essential for lethality in mice. When E3L is partially or wholly deleted, the virus can grow in cell culture, but it is no longer pathogenic. Recent research has demonstrated that the N terminal domain of the vaccinia E3L is a Z-DNA binding protein. This work stems from crystal structures of other related proteins that were co-crystallized with Z-DNA. E3L has the same group of amino acid residues that are essential for Z-DNA recognition as are found in these related proteins. Mutations in E3L that prevent its binding to Z-DNA render the virus harmless in the mouse model. In this work, an attempt will be made to find a small molecule that binds to the Z-DNA binding pocket of the E3L molecule. It is anticipated that binding to that pocket will prevent the E3L molecule from binding to Z-DNA and hence it will lose its pathogenicity. Variola, the agent of smallpox, has a virtually identical E3L molecule, and it is likely that it is also essential for its pathogenicity. A small molecule capable of binding with high affinity to the Z-DNA binding pocket may provide a therapy for preventing smallpox. In the present application, libraries of small molecules will be screened in an effort to obtain one that blocks the action of E3L. This will be tested initially to prevent the pathogenicity of vaccinia in the mouse model. This should ultimately lead to the prevention of pathogenicity of Variola, which can be tested by others in an available primate model.